ArticleDiabetes2020
Repurposing Doxepin to Ameliorate Steatosis and Hyperglycemia by Activating FAM3A Signaling Pathway.
Article in Diabetes, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 29 citations in OpenAlex.
- FAM3A Inhibits Plasma Triglyceride Levels via Microvasculature-Involved Enhancement of VLDL-Triglyceride Hydrolysis and Lipid Uptake.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Hepatic Gluconeogenesis and the Antidepressant Effects of Exercise: A Narrative Review.Metabolites · 2026Review
- An update on current type 2 diabetes mellitus (T2DM) druggable targets and drugs targeting them.Molecular diversity · 2025Review
- Hepatic ENTPD5 Is Critical for Maintaining Metabolic Homeostasis and Promoting Brown Adipose Tissue Thermogenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Emerging roles of the acid sphingomyelinase/ceramide pathway in metabolic and cardiovascular diseases: Mechanistic insights and therapeutic implications.World journal of cardiology · 2025Review
- PANX1-mediated ATP release confers FAM3A's suppression effects on hepatic gluconeogenesis and lipogenesis.Military Medical Research · 2024Article
- FAM3A Deficiency - Induced Mitochondrial Dysfunction Underlies Post-Infarct Mortality and Heart Failure.Journal of cardiovascular translational research · 2024Article
- Oxyresveratrol as a novel ferroptosis inducer exhibits anticancer activity against breast cancer via the EGFR/PI3K/AKT/GPX4 signalling axis.Frontiers in pharmacology · 2024Article
- FAM3 family genes are associated with prognostic value of human cancer: a pan-cancer analysis.Scientific reports · 2023Article
- FAM3A reshapes VSMC fate specification in abdominal aortic aneurysm by regulating KLF4 ubiquitination.Nature communications · 2023Article
- Ranuncoside's attenuation of scopolamine-induced memory impairment in mice via Nrf2 and NF-ĸB signaling.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2023Article
- FAM3A mediates the phenotypic switch of human aortic smooth muscle cells stimulated with oxidised low-density lipoprotein by influencing the PI3K-AKT pathway.In vitro cellular & developmental biology. Animal · 2023Article
- Identification of disease-related genes and construction of a gene co-expression database in non-alcoholic fatty liver disease.Frontiers in genetics · 2023Article
- FAM3A Ameliorates Brain Impairment Induced by Hypoxia-Ischemia in Neonatal Rat.Cellular and molecular neurobiology · 2023Article
- Connecting insufficient sleep and insomnia with metabolic dysfunction.Annals of the New York Academy of Sciences · 2023Review
- ATP Secretion and Metabolism in Regulating Pancreatic Beta Cell Functions and Hepatic Glycolipid Metabolism.Frontiers in physiology · 2022Review
- Doxepin Exacerbates Renal Damage, Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Urinary Chromium Loss in Obese Mice.Pharmaceuticals (Basel, Switzerland) · 2021Article
- The Protective Effects and Mechanism of Doxepin on Radiation-Induced Lung Injury in Rats.Dose-response : a publication of International Hormesis SocietyArticle
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mitochondrial protein FAM3A suppresses hepatic gluconeogenesis and lipogenesis. This study aimed to screen drug(s) that activates FAM3A expression and evaluate its effect(s) on hyperglycemia and steatosis. Drug-repurposing methodology predicted that antidepressive drug doxepin was among the drugs that potentially activated FAM3A expression. Doxepin was further validated to stimulate the translocation of transcription factor HNF4α from the cytoplasm into the nucleus, where it promoted FAM3A transcription to enhance ATP synthesis, suppress gluconeogenesis, and reduce lipid deposition in hepatocytes. HNF4α antagonism or FAM3A deficiency blunted doxepin-induced suppression on gluconeogenesis and lipid deposition in hepatocytes. Doxepin administration attenuated hyperglycemia, steatosis, and obesity in obese diabetic mice with upregulated FAM3A expression in liver and brown adipose tissues (BAT). Notably, doxepin failed to correct dysregulated glucose and lipid metabolism in FAM3A-deficient mice fed on high-fat diet. Doxepin's effects on ATP production, Akt activation, gluconeogenesis, and lipogenesis repression were also blunted in FAM3A-deficient mouse livers. In conclusion, FAM3A is a therapeutic target for diabetes and steatosis. Antidepressive drug doxepin activates FAM3A signaling pathways in liver and BAT to improve hyperglycemia and steatosis of obese diabetic mice. Doxepin might be preferentially recommended as an antidepressive drug in potential treatment of patients with diabetes complicated with depression.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.